Endothelin-1 Drives Epithelial-Mesenchymal Transition in Hypertensive Nephroangiosclerosis.
Endothelin-1 Drives Epithelial-Mesenchymal Transition in Hypertensive Nephroangiosclerosis.
复制标题
DOI：
10.1161/jaha.116.003888
复制
发表时间：
2016-07-21
影响因子：
5.4
通讯作者：
Rossi GP
中科院分区：
文献类型：
--
作者：
Seccia TM;Caroccia B;Gioco F;Piazza M;Buccella V;Guidolin D;Guerzoni E;Montini B;Petrelli L;Pagnin E;Ravarotto V;Belloni AS;Calò LA;Rossi GP
肾小管间质纤维化是大多数肾脏疾病的最终结局，涉及上皮间充质转化（EMT）的激活。内皮素- 1 （ET - 1）激活癌细胞中的EMT，但它是否驱动肾脏中的EMT尚不清楚。因此，我们验证了小管间质纤维化涉及ET‐1驱动的EMT的假设。转基因TG[mRen2]27 （TGRen2）大鼠发展为暴发性血管紧张素II依赖性高血压，伴有明显的心血管和肾脏损害，给予针对ET‐1和/或血管紧张素II受体的药物治疗或不治疗（对照组）。检测E‐cadherin和α‐平滑肌肌动蛋白（α‐sma）的表达变化作为肾脏EMT的标志物。在表达ETB受体亚型的人肾HK‐2近端小管细胞中，我们还研究了ET‐1有或没有ET‐1拮抗剂的影响。对照TGRen2大鼠肾纤维化的发生与EMT相关，E‐cadherin的减少和α - sma的表达增加证明了这一点。厄贝沙坦和混合ET - 1受体拮抗剂波生坦以不依赖血压的方式阻止了这些变化（与对照组相比，两者的P < 0.001）。在HK‐2细胞中，ET‐1抑制了E‐cadherin的表达，增加了α - sma的表达（P < 0.01），增加了胶原合成和金属蛋白酶活性（P < 0.005，与未处理的细胞相比）。选择性乙脑受体拮抗剂BQ‐788可预防所有变化。研究还发现了Rho激酶信号通路和Yes相关蛋白的去磷酸化参与EMT的证据。在血管紧张素ii依赖性高血压中，ET - 1通过ETB受体、Rho激酶和Yes相关蛋白作用诱导EMT，从而导致肾纤维化。
Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin‐1 (ET‐1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET‐1. Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II–dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET‐1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of E‐cadherin and α‐smooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HK‐2 proximal tubular cells expressing the ETB receptor subtype, the effects of ET‐1 with or without ET‐1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased E‐cadherin and increased αSMA expression. Irbesartan and the mixed ET‐1 receptor antagonist bosentan prevented these changes in a blood pressure–independent fashion (P < 0.001 for both versus controls). In HK‐2 cells ET‐1 blunted E‐cadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ETB receptor antagonist BQ‐788. Evidence for involvement of the Rho‐kinase signaling pathway and dephosphorylation of Yes‐associated protein in EMT was also found. In angiotensin II–dependent hypertension, ET‐1 acting via ETB receptors and the Rho‐kinase and Yes‐associated protein induces EMT and thereby renal fibrosis.